DESCRIPTION (Taken from the applicant=s abstract): About 1% of the US population (2.1 million people) have rheumatoid arthritis(RA). The most common RA is a late-onset disease, beginning at middle age with increased frequency in adulthood. While the exact causes for the different types of RA vary, the symptoms in each (swelling, redness, heat and pain) are reminiscent of the cardinal signs of inflammation. The social and financial impact of RA on both individual and nation are substantial, and due primarily to the debilitating symptoms of the disease (daily joint injury and inflammation). One approach to relieving the discomfort of this disease, is to treat the symptoms, i.e. an anti-inflammatory treatment. Our knowledge of the cellular mechanisms involved in the resolution of acute inflammatory reactions that are neutrophil-driven is limited. Lipoxin A4 is a potent lipid-signaling molecule that mediates protective actions. This eicosanoid provides a model system for the evaluation of key targets in anti-inflammatory pathways. This research proposal is intended to test the hypothesis that in vivo, ALXR is a ligand-activated cell-surface receptor that tranduces the anti-inflammatory LXA4 signal, in part via a nuclear receptor pathway, to regulate the dynamics of an acute inflammatory reaction. A combined approach using transgenics, eicosanoid chemistry and molecular and cell biology techniques will be used to evaluate three main aspects of LXA. signaling in mature myeloid cells: 1 .) To establish, in vivo, that the Lipoxin A4 receptor (ALXR) is a primary site of action for LXA4 and aspirin-triggered lipoxins. 2.) Identify nuclear events associated with LXA4 signaling and understand how these events counter-regulate pro-inflammatory transcription factors; and 3.) Use a wound-healing animal model to understand how ALXR modulates the dynamics of an acute inflammatory reaction towards resolution. The control of leukocytes is important not only for therapeutic use in disorders associated with uncontrolled inflammation (e.g., R A), but also has potential as a preventative measure against second organ injury during routine surgical procedures. Knowledge of endogenous anti-inflammatory lipid mediators and their sites of action could provide a platform for new therapeutic interventions.